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Single-cell multiomic integration identifies widespread, cell-type resolved fetal reactivation in the diseased human heart

ABSTRACT: Background: As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life. Results: We generate an integrated multiomic atlas of human cardiac cells, combining newly generated and publicly available single-nucleus RNA sequencing datasets from 299 donors and single nucleus ATAC-seq datasets from 106 donors. Developmental and disease-associated processes drive far more extensive molecular remodeling than sex-associated or aging-dependent effects. Across nearly all cardiac cell types, developmental and disease-driven changes exhibit strong overlap at both the transcriptomic and epigenomic levels, revealing widespread reactivation of fetal-associated gene programs beyond cardiomyocytes. Both cardiac development and disease show convergent shifts in intercellular communication, including increased TGFβ signaling. Integration of gene expression and chromatin accessibility data reveals putative cell-type–specific transcriptional factors driving fetal reactivation in major cardiac diseases. Spatial transcriptomics data orthogonally identifies localization of this fetal reactivation signature within spatially distinct niches in ischemic and fibrotic zones of acute myocardial infarction. Finally, we construct a cell-type–resolved enhancer-to-gene linkage map that refines the association of dilated and hypertrophic cardiomyopathy genetic risk loci to downstream target genes. Conclusions: This study presents a comprehensive multimodal, cell-type–resolved atlas of the human heart, providing a foundation for understanding human cardiac gene regulation across the human lifespan and in cardiac diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290367 | GEO | 2026/03/15

REPOSITORIES: GEO

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Project description:BACKGROUND: Single ventricle congenital heart disease (SVCHD) is a severe form of cardiac malformation in which there is only one functional ventricle. The Fontan operation is the current standard of care for SVCHD. Almost all patients who have undergone the Fontan operation develop liver fibrosis at a young age, resulting in a condition known as Fontan-associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, hindering development of effective therapies.OBJECTIVES: We aimed to present a comprehensive multiomic analysis of human FALD, thereby revealing the fundamental biology and pathogenesis of FALD. METHODS: We recently generated a single-cell transcriptomic and epigenomic atlas of human FALD using snRNA-ATAC-seq, which revealed profound metabolic reprogramming in FALD. Here we applied liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples/biopsies from age and gender-matched healthy donors and FALD patients (n=12 per group). Extracted liver metabolites were analyzed by C18 high performance liquid chromatography (HPLC) and hydrophilic interaction chromatography (HILIC) followed by high resolution MS on Orbitrap. Statistical and bioinformatics analyses were performed to identify altered metabolites and metabolic pathways in FALD. These results were integrated with recently published snRNA-ATAC-seq and serum metabolomics datasets to present a comprehensive multiomic atlas of FALD. RESULTS: We discovered profound metabolic abnormalities in livers of patients with early-stage FALD, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, TCA cycle, ketone body metabolism and bile acids metabolism. Integrated analyses with liver snRNA-ATAC-seq and serum metabolomics data unveiled the transcriptional mechanisms driving this metabolic reprogramming and the crosstalk between liver and the rest of the body. Comparison with human metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH) revealed dysregulated amino acid metabolism as a common metabolic abnormality. CONCLUSIONS: Our comprehensive multiomic atlas of human FALD reveals the fundamental biology and pathogenesis mechanisms of FALD.

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Single-cell multiomic integration identifies widespread, cell-type resolved fetal reactivation in the diseased human heart

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